The influence of anatomical, developmental and degenerative factors on the function of synaptically expressed ionotropic glutamate receptors was assessed in murine models. Recordings were obtained in whole cell configuration from principal cells in layer II of acutely prepared slices of anterior piriform cortex (APC). Synaptic currents mediated by AMPARs and NMDARs were elicited by evoked stimulation and isolated on the basis of differences in pharmacological and kinetic characteristics of each receptor type. The relative current contribution in synaptic populations was assessed by an NMDA/AMPA ratio calculated from measurement of evoked currents. AMPAR currents were characterized at single synapses by mEPSCs and response to minimal stimulation.
Afferent and intrinsic axonal fiber tracts were stimulated to elicit currents at lateral olfactory tract (LOT) and association (ASSN) synapses, two anatomically and physiologically distinct populations of synapses. Paired pulse responses at 50 ms ISI revealed differences in the amount of facilitation between both synaptic populations. Synaptic transmission mediated by AMPAR function was assessed by minimal stimulation and determined to be equivalent in amplitude between LOT and ASSN synapses, although differences in AMPAR kinetic characteristics were detected between pathways. The NMDA/AMPA ratio was decreased at LOT compared to ASSN synapses. Differences found in the relative NMDAR and AMPAR complement and similarities in AMPAR function suggest differences in NMDAR function between LOT and ASSN synapses. Kinetic differences detected in AMPAR-mediated currents suggest different AMPAR complements are also expressed at both pathways.
Synaptic receptor function was characterized in a mouse model for developmental intellectual disability, the Fmr1-KO. Synaptic NMDAR and AMPAR function was assessed at ASSN synapses in 3-6 month old Fmr1- KO and WT littermates. The NMDA/AMPA ratio was reduced at ASSN synapses of the Fmr1-KO and similar amplitudes in AMPAR-mediated mEPSCs were observed in both groups. No differences were observed in voltage sensitivities or kinetic characteristics of either NMDAR or AMPAR currents. These findings suggest a reduction in NMDAR function at these synapses in the Fmr1- KO compared to WT.
The effect of aging on NMDAR and AMPAR function was assessed at LOT and ASSN synapses in 3-28 month old mice. A significant reduction in AMPAR-mediated mEPSC amplitude was observed in 24-28 month old mice. No age related difference was detected in the NMDA/AMPA ratio or paired pulse ratio. These findings suggest that concomitant downregulation of AMPAR and NMDAR function occurs at both LOT and ASSN synapses in aged mice.
The relative and absolute function of NMDARs and AMPARs at LOT and ASSN synapses were found to be differentially affected in all three comparisons. Reduction of currents mediated by one or both synaptic receptor types were observed in all conditions. Hypofunction of one or both receptor type and the relative ratios thereof may explain specific characteristics of LTP induction and expression in APC, and learned behaviors mediated by this synaptic plasticity, in anatomical and etiological conditions.
|Advisor:||Larson, John, Alford, Simon|
|Commitee:||Alford, Simon, Larson, John, Leonard, John, Malchow, Paul, Smalheiser, Neil|
|School:||University of Illinois at Chicago|
|School Location:||United States -- Illinois|
|Source:||DAI-B 74/06(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology, Physiology|
|Keywords:||AMPA receptors, Cognition, Electrophysiology, Glutamate, NMDA receptors, Piriform cortex|
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